We are studying the basis for increased tuberculosis (TB) susceptibility in diabetes mellitus (DM). The global population-attributable TB risk conferred by DM equals that of AIDS. Diabetes is a leading cause of acquired TB susceptibility in India and China, which have rapidly rising rates of DM on top of already high rates of TB. Major findings in work supported by HL081149 are that mice with chronic hyperglycemia, modeling DM, are more susceptible to TB and have a delayed innate response to aerosol Mycobacterium tuberculosis (Mtb) challenge which is followed by dysregulated and excessive T cell activation. In the last 4 years of this project we discovered that alveolar macrophages (AM?) from diabetic mice have reduced expression of the receptors MARCO and CD14 that are involved in the recognition of the Mtb cell wall component trehalose dimycolate. This may explain the delayed innate response in vivo. We also discovered that chronic hyperglycemia causes RAGE-dependent pre-activation of nave T cells that we attribute to chromatin decondensation. This may explain the excess T cell cytokine production characteristic of TB in diabetic mice and people. In the competing renewal we will investigate the mechanistic basis for the delayed innate response to Mtb in diabetic mice and the effects of diabetes on T cell expansion and exhaustion during TB (using retrogenic mice). We plan novel studies using Mtb mutants as sensors of the bacterial environment in diabetic vs non-diabetic hosts with TB. This provides a unique perspective to understand how changes in cellular immunity cause by diabetes impact bacterial fitness. Building on evidence that diabetes-associated dyslipidemias also impact TB defense, we will apply the same experimental approaches to investigate protective immunity in mice with elevated cholesterol or elevated triglycerides plus free fatty acids, with or without comorbid diabetes. This models type 2 DM, the predominant form in people. Our goal is to generate fundamental knowledge about TB susceptibility in diabetes that can be translated to new treatments. To that end, we will investigate the impact of the host- directed therapy candidate metformin on TB defense in the context of diabetes. This will enhance understanding of the protective mechanism of metformin while at the same time revealing pathways linked to TB susceptibility in diabetes. Despite its significance, the impact of diabetes and dyslipidemias on TB defense has received little attention from basic scientists. We are addressing a major gap in knowledge and at the same time using our models to reveal fundamental elements of the host-pathogen interaction in TB.